Understanding the molecular mechanisms governing beta cell proliferation has important ramification for fostering beta cell regeneration and the treatment of diabetes. Studies supported by a pilot 2 year collaborative grant established that cyclin D2-mediated proliferation was essential in the regulation of postnatal beta cell mass. We also demonstrated that the transition of beta cells from quiescence to proliferation is controlled by p27, a negative regulator of cyclin D2-mediated proliferation. We showed that quiescent beta cells accumulate p27 and disabling p27 in these cells allows them to divide. Thus, the cellular abundance of p27 is a critical determinant of whether a beta cell divides or remains quiescent. We now present preliminary data to demonstrate that ubiquitin ligase-mediated degradation pathways regulate the cellular abundance of p27 and the progression of beta cell proliferation. We also show that pathways regulating p27 turnover could be involved in accumulating p27 in beta cells of animal models of type 2 diabetes. In the next five years we will endeavor to integrate mechanisms of p27 turnover and their role in metabolic disorders. We propose to study: Aim 1, the ubiquitin ligase-mediated degradation pathways that regulate cell cycle progression of beta cells and their role in beta cell compensatory growth in insulin resistance animal models;in Aim 2, to utilize p27 degradation pathways to promote beta cell expansion/regeneration; Aim 3, how p27 degradation pathways contribute to beta cell failure during the development of type 2 diabetes in animal models;Aim 4, to examine whether targeting p27 could be beneficial for cell-based therapies in which the extent of cell proliferation could have potential benefit. These studies will be carried out using null mouse mutants, beta cell-specific inducible transgenic mice, and cultured islet, using methods that are fully implemented in the laboratory. The goal of this work is to find a therapeutic approach for modifying p27 function and we hope that by identifying mechanisms of p27 turnover, new ways to modulate its function in a controlled fashion can be found.